1. Field of the Invention
The invention relates to pyrrole-containing peptidomimetic compounds that inhibit the enzymatic activity of picornaviral 3C proteases, especially rhinovirus 3C proteases (RVPs), and that retard viral growth in cell culture. The invention also relates to the use of these compounds in pharmaceutical compositions, methods of treatment of rhinoviral infections using these compounds and compositions, and processes for the synthesis of these compounds and compounds useful in the syntheses thereof.
2. Related Background Art
The picornaviruses are a family of tiny non-enveloped positive-stranded RNA-containing viruses that infect humans and other animals. These viruses include the human rhinoviruses, human polioviruses, human coxsackieviruses, human echoviruses, human and bovine enteroviruses, encephalomyocarditis viruses, meningitis virus, foot and mouth viruses, hepatitis A virus, and others. The human rhinoviruses are a major cause of the common cold. To date, there are no effective therapies on the market that cure the common cold, only treatments that relieve the symptoms.
Picornaviral infections may be treated by inhibiting the proteolytic picornaviral 3C enzymes. These enzymes are required for the natural maturation of the picornaviruses. They are responsible for the autocatalytic cleavage of the genomic, large polyprotein into the essential viral proteins. Members of the 3C protease family are cysteine proteases, where the sulfhydryl group most often cleaves the glutamine-glycine amide bond. Inhibition of 3C proteases is believed to block proteolytic cleavage of the viral polyprotein, which in turn can retard the maturation and replication of the viruses by interfering with viral particle production. Therefore, inhibiting the processing of this cysteine protease with selective small molecules that are specifically recognized should represent an important and useful approach to treat and cure viral infections of this nature and, in particular, the common cold.
Some small-molecule inhibitors of the enzymatic activity of picornaviral 3C proteases (i.e., antipicornaviral compounds) have been recently discovered. See, for example: U.S. Pat. No. 5,856,530; U.S. Pat. No. 5,962,487; U.S. Pat. No. 6,020,371; and U.S. patent application Ser. No. 09/301,977, filed Apr. 29, 1999, by Dragovich et al. See also: Dragovich et al., xe2x80x9cStructure-Based Design, Synthesis, and Biological Evaluation of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . ,xe2x80x9d J. Med. Chem. (1999), Vol. 42, No. 7, 1203-1212, 1213-1224; and Dragovich et al., xe2x80x9cSolid-phase Synthesis of Irreversible Human Rhinovirus 3C Protease Inhibitors . . . ,xe2x80x9d Bioorg. and Med. Chem. (1999), Vol. 7, 589-598. There remains a desire, to discover small-molecule compounds that are especially potent antipicornaviral agents.
Inhibitors of other related cysteine proteases such as cathepsins have been described in, e.g., U.S. Pat. No. 5,374,623; U.S. Pat. No. 5,498,616; and WIPO International Publication Nos. WO 94/04172, WO 95/15749, WO 97/19231, and WO 97/49668. There yet remains a need for inhibitors targeting the picornaviral 3C cysteine protease with desirable pharmaceutical properties, such as high specificity, good therapeutic index or low toxicity.
This invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general Formula I: 
wherein:
Ra is an alkylcarbonylalkyl, cycloalkylcarbonylalkyl, arylcarbonylalkyl, heteroarylcarbonylalkyl, alkylcarbonylaminoalkyl, cycloalkylcarbonylaminoalkyl, heterocycloalkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, heteroarylcarbonylaminoalkyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl group, where each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents;
Rb is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
Rd is H, halo, hydroxyl, or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
Rc is a moiety having the formula: 
Re and Rf are each independently H or a lower alkyl group;
m is 0 or 1, provided that when m is 1, Ra is not an amino-substituted alkylcarbonylalkyl or amino-substituted alkylcarbonylaminoalkyl group, and when m is 0, Ra is selected from an alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, heterocycloalkylaminocarbonylalkyl, arylaminocarbonylalkyl, heteroarylaminocarbonylalkyl and heteroarylcarbonylaminoalkyl group, provided that Ra is not substituted indolecarbonylaminoalkyl;
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(Rg)(Rh), N(Ri), S, S(O), S(O)2, or O, and when p is 0, A2 is C(Rg)(Rh)(Ri), N(Rg)(Ri), S(Rg), S(O)(Rg), S(O)2(Rg), or O(Rg), where each Rg, Rh and Ri is independently H or a lower alkyl group;
each A3 present is each independently C(Rg)(Rh), N(Ri), S, S(O), S(O)2, or O, where each Rg, Rh and Ri is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(Rj), C(Rg)(Rh), or O, and when p is 0 (i.e., A3 is not present), A4 is N(Rj)(Rk), C(Rg)(Rh)(Ri), and O(Rk), where each Rg, Rh and Ri is independently H or a lower alkyl group, each Rj is H, an alkyl, aryl, or acyl group, and each Rk is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present (i.e., m=1) and a hydrogen atom when A2 is absent (i.e., m=0); and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R1, xe2x80x94CO2R1, xe2x80x94CN, xe2x80x94C(O)NR1Rm, xe2x80x94C(O)NR1ORm, xe2x80x94C(S)R1, xe2x80x94C(S)OR1 xe2x80x94C(S)NR1Rm, xe2x80x94C(xe2x95x90NR1)Rm, xe2x80x94C(xe2x95x90NR1)ORm, xe2x80x94NO2, xe2x80x94SORm, xe2x80x94SO2R1, xe2x80x94SO2NR1Rm, xe2x80x94SO2(NR1)(ORm), xe2x80x94SONR1, xe2x80x94SO3R1, xe2x80x94PO(OR1)2, xe2x80x94PO(OR1)(ORm), xe2x80x94PO(NR1Rm)(ORn), xe2x80x94PO(NR1Rm)(NRnR0), xe2x80x94C(O)NR1NRmRn, xe2x80x94C(S)NR1NRmRn, where R1, Rm, Rn and Ro are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R1, Rm, Rn and Ro, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and Rd, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
In another embodiment of the compounds of the above Formula I,
A1 is CH or N;
A2 is C(Rg)(Rh), N(Ri), S, S(O), S(O)2, or O, where each Rg, Rh and Ri is independently H or a lower alkyl group;
each A3 present is independently C(Rg(Rh), N(Ri), S, S(O), S(O)2, or O, where each Rg, Rh and Ri is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(Rj), C(Rg)(Rh), or O, and when p is 0, A4 is N(RJ)(Rk), C(Rg)(Rh)(Ri), and O(Rk), where each Rg, Rh and Ri is independently H or a lower alkyl group, each Rj is H, an alkyl, aryl, or acyl group, and each Rk is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R1, xe2x80x94CO2R1, xe2x80x94CN, xe2x80x94C(O)NR1Rm, xe2x80x94C(O)NR1ORm, xe2x80x94C(S)R1, xe2x80x94C(S)NR1Rm, xe2x80x94NO2, xe2x80x94SORm, xe2x80x94SO2R1, xe2x80x94SO2NR1Rm, xe2x80x94SO2(NR1)(ORm), xe2x80x94SONR1, xe2x80x94SO3R1, xe2x80x94PO(OR1)2, xe2x80x94PO(OR1)(ORm), xe2x80x94PO(NR1Rm)(ORn), xe2x80x94PO(NR1Rm)(NRnRo), xe2x80x94C(O)NR1NRmRn, xe2x80x94C(S)NR1NRmRn, where R1, Rm, Rn and Ro are each independently H, an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aaryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R1, Rm, Rn and Ro, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above.
One embodiment of this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general Formula II: 
wherein Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, n is 1, 2 or 3, m is 1, Rx and Ry are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents, and Rb, Rc, Rd, Z and Z1 are as defined above, provided that Raxe2x80x2 is not an amino-substituted alkyl group.
Another embodiment of this invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general Formula III: 
wherein Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, n is 1, 2 or 3, m is 1, Rx and Ry are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents, and Rb, Rc, Rd, Z and Z1 are as defined above, provided that Raxe2x80x2 is not an amino-substituted alkyl group.
This invention also relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the following general Formula IV: 
wherein Raxe2x80x2 is an alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, n is 1, 2 or 3, Rx and Ry are each independently selected from H and an alkyl group, unsubstituted or substituted with one or more suitable substituents, and Rb, Rc, Rd, Z and Z1 are as defined above.
This invention relates to compounds useful for inhibiting the activity of picornaviral 3C proteases having the general Formula V: 
wherein:
W is CH or N;
R1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R2 and R3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with a suitable substituent;
or R1 together with R2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with a suitable substituent;
R4 and R6 are each independently H or a lower alkyl group, unsubstituted or substituted with a suitable substituent;
R5 is H or an alkyl group, unsubstituted or substituted with a suitable substituent;
R7 is a moiety having the formula: 
wherein:
R8 and R9 are each independently H or a lower alkyl group;
m is 0 or 1, provided that when W is N, m is 0 and R1 together with R2 form an aryl ring, the aryl ring is unsubstituted (e.g., R1 together with R2 and the pyrrole to which they are bound do not form a substituted indole);
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)OR15, xe2x80x94C(S)NR15R16, xe2x80x94C(xe2x95x90NR15)R16, xe2x80x94C(xe2x95x90NR15)OR16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group).
In another embodiment of the compounds of Formula V,
A1 is CH or N;
A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)NR15R16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above.
In the compounds of the above-described Formulas I-V, Rc and R7 are defined to provide structures where m is 1 and p is 1-5 (i.e., both A2and A3 are present), m is 0 and p is 0 (i.e., both A2 and A3 are absent), m is 0 and p is 1-5 (i.e., A2 is absent and A3 is present) and m is 1 and p is 0 (i.e., A2 is present and A3 is absent). Accordingly, one of ordinary skill in the are will recognize that when both A2 and A3 are present (m is 1 and p is 1-5), the dotted line between A1 and A2 represents a bond and the dotted line between A2 and A3 represents a bond. When both A2 and A3 are absent (m is 0 and p is 0) A2, A3 and the dotted line between these substituents are not present and the remaining dotted line in the structure between A1 and A2 represents a hydrogen (e.g., A1 is CH2 or NH). In embodiments of this invention when A2 is absent and A3 is present (m is 0 and p is 1-5), the dotted line between A1 and A2 represents a hydrogen and the dotted line between A2 and A3 represents a hydrogen (e.g., A1 is CH2 or NH and A3 is CH(Rg)(Rh), NH(Ri), SH, S(O)H, S(O)2H, or OH or CH(R10)(R11), NH(R12), SH, S(O)H, S(O)2H, or OH); and when A2 is present and A3 is absent (m is 1 and p is 0), the dotted line between A1 and A2 represents a bond and A2 is C(Rg)(Rh)(Ri), N(Rg)(Ri), S(Rg), S(O)(Rg), S(O)2(Rg), or O(Rg) or A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) or the dotted line between A2 and A3 represents a hydrogen and A2 is CH(Rg)(Rh), NH(Ri), SH, S(O)H, S(O)2H, or OH or A2 is CH(R10)(R11), NH(R12), SH, S(O)H, S(O)2H, or OH. In preferred embodiments of the compounds of Formula I-V of this invention, m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2, A2 and A3 are both C(Rg)(Rh) or C(R10)(R11), respectively. More preferably, m is 1 and p is 1.
In addition to compounds of the Formulas I-V, antipicornaviral agents of the invention include prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates of such compounds.
In accordance with a convention used in the art, 
is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
As used herein, the term xe2x80x9calkylxe2x80x9d represents a straight- or branched-chain saturated or unsaturated hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below. A C1-C6 alkyl represents an alkyl substituent containing 1 to 6 carbon atoms. Exemplary alkyl substituents include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, pentenyl, ethynyl, butynyl, propynyl (propargyl, isopropynyl), pentynyl, hexynyl and the like. The term xe2x80x9clower alkylxe2x80x9d refers to an alkyl group containing from 1 to 4 carbon atoms.
xe2x80x9cCycloalkylxe2x80x9d represents a group comprising a non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms which may be unsubstituted or substituted by one or more of the substituents described below and may be saturated or unsaturated. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, that may be fully saturated or partially unsaturated. Illustrative examples of cycloalkyl groups include the following: 
xe2x80x9cHeterocycloalkylxe2x80x9d represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or partially unsaturated, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more of the substituents described below. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3 -oxathiolanyl, 1 ,3-oxathianyl, 1,3-dithianyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, azabicyclo[4.3.0]nonyl, oxabicyclo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like. Illustrative examples of heterocycloalkyl groups include the following moieties: 
wherein R is H, alkyl or hydroxyl.
xe2x80x9cArylxe2x80x9d represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more of the substituents described below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include the following moieties: 
xe2x80x9cHeteroarylxe2x80x9d represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more of the substituents described below. As used herein, the term xe2x80x9cheteroarylxe2x80x9d is also intended to encompass the N-oxide derivative (or N-oxide derivatives, if the heteroaryl group contains more than one nitrogen such that more than one N-oxide derivative may be formed) of the nitrogen-containing heteroaryl groups described herein. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl. Illustrative examples of N-oxide derivatives of heteroaryl groups include, but are not limited to, pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide, isoquinolyl N-oxide, and quinolyl N-oxide. Further examples of heteroaryl groups include the following moieties: 
wherein R is H, alkyl or hydroxyl.
The term xe2x80x9csuitable substituentxe2x80x9d represents a substituent that is optionally present on any of the above alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups, described herein, and is selected from alkyl (except for alkyl) haloalkyl, haloaryl, halocycloalkyl, haloheterocycloalkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, hydroxamino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, and heteroarylthio groups, where any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted with one or more substituents selected from nitro, amino, cyano, halo, haloalkyl, haloaryl, hydroxyl, keto, hydroxamino, alkylamino, dialkylamino, mercapto, and unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy, alkylthio or arylthio groups and where any of the aryl or heteroaryl moieties may be substituted with alkylenedioxy. Preferred xe2x80x9csuitable substituentsxe2x80x9d include alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heteroaryloxy, and carboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any of the above substituents may be optionally substituted by one or more of alkyl (except for alkyl), halo, haloalkyl, aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with one or more subsituents, (e.g., haloaryl), independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups.
The terms xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represent chloro, fluoro, bromo or iodo substituents. xe2x80x9cHeterocyclexe2x80x9d is intended to mean a heteroaryl or heterocycloalkyl group. xe2x80x9cAcylxe2x80x9d is intended to mean a xe2x80x94C(O)xe2x80x94R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cAcyloxyxe2x80x9d is intended to mean an xe2x80x94OC(O)xe2x80x94R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cThioacylxe2x80x9d is intended to mean a xe2x80x94C(S)xe2x80x94R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. xe2x80x9cSulfonylxe2x80x9d is intended to mean an xe2x80x94SO2xe2x80x94 biradical. xe2x80x9cSulfenylxe2x80x9d is intended to mean an xe2x80x94SOxe2x80x94 biradical. xe2x80x9cSulfoxe2x80x9d is intended to mean an xe2x80x94SO2H radical. Sulfoxide is intended to mean a xe2x80x94SO3xe2x88x92 radical xe2x80x9cHydroxyxe2x80x9d is intended to mean the radical xe2x80x94OH. xe2x80x9cAminexe2x80x9d or xe2x80x9caminoxe2x80x9d is intended to mean the radical xe2x80x94NH2. xe2x80x9cAlkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NHRa, wherein Ra is an alkyl group. xe2x80x9cDialkylaminoxe2x80x9d is intended to mean the radical xe2x80x94NRaRb, wherein Ra and Rb are each independently an alkyl group, and is intended to include heterocycloalkyl groups, wherein Ra and Rb, taken together, form a heterocyclic ring that includes the amine nitrogen. xe2x80x9cHydroxaminoxe2x80x9d is intended to mean the radical xe2x80x94Nxe2x80x94OH. xe2x80x9cAlkoxyxe2x80x9d is intended to mean the radical xe2x80x94ORa, wherein Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. xe2x80x9cLower alkoxyxe2x80x9d groups have alkyl moieties having from 1 to 4 carbons. xe2x80x9cAlkylenedioxyxe2x80x9d is intended to mean the divalent radical xe2x80x94ORaOxe2x80x94 which is bonded to adjacent atoms on an aryl or heteroaryl moiety (e.g., adjacent atoms on a phenyl or naphthyl ring) , wherein Ra is a lower alkyl group. xe2x80x9cAlkoxycarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)ORa, wherein Ra is an alkyl group. xe2x80x9cAlkylsulfonylxe2x80x9d is intended to mean the radical xe2x80x94SO2Ra, wherein Ra is an alkyl group. xe2x80x9cAlkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NHRa, wherein Ra is an alkyl group. xe2x80x9cDialkylaminocarbonylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NRaRb, wherein Ra and Rb are each independently an alkyl group. xe2x80x9cMercaptoxe2x80x9d is intended to mean the radical xe2x80x94SH. xe2x80x9cAlkylthioxe2x80x9d is intended to mean the radical xe2x80x94SRa, wherein Ra is an alkyl group. xe2x80x9cCarboxylxe2x80x9d is intended to mean the radical xe2x80x94C(O)OH. xe2x80x9cKetoxe2x80x9d or xe2x80x9coxoxe2x80x9d is intended to mean the radicalxe2x95x90O. xe2x80x9cThioketoxe2x80x9d is intended to mean the radicalxe2x95x90S. xe2x80x9cCarbamoylxe2x80x9d is intended to mean the radical xe2x80x94C(O)NH2. xe2x80x9cCycloalkylalkylxe2x80x9d is intended to mean the radical -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above, and is exemplified by the bonding arrangement present in the groups xe2x80x94CH2-cyclohexane or xe2x80x94CH2-cyclohexene. xe2x80x9cArylalkylxe2x80x9d is intended to mean the radical -alkylaryl, wherein alkyl and aryl are defined as above, and is exemplified by the bonding arrangement present in a benzyl group. xe2x80x9cAminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O) NH2 and is exemplified by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NH2. xe2x80x9cAlkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NHRa, wherein Ra is an alkyl group and is exemplified by the bonding arrangement present in the group xe2x80x94CH2CH2C(O)NHCH3. xe2x80x9cAlkylcarbonylaminoalkylxe2x80x9d is intended to mean the radical -alkylNHC(O)-alkyl and is exemplified by the bonding arrangement present in the group xe2x80x94CH2NHC(O)CH3. xe2x80x9cDialkylaminocarbonylalkylxe2x80x9d is intended to mean the radical -alkylC(O)NRaRb, wherein Ra and Rb are each independently an alkyl group. xe2x80x9cAryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORc, wherein Rc is an aryl group. xe2x80x9cHeteroaryloxyxe2x80x9d is intended to mean the radical xe2x80x94ORd, wherein Rd is a heteroaryl group. xe2x80x9cArylthioxe2x80x9d is intended to mean the radical xe2x80x94SRc, wherein Rc is an aryl group. xe2x80x9cHeteroarylthioxe2x80x9d is intended to mean the radical xe2x80x94SRd, wherein Rd is a heteroaryl group.
The alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups and the substituents containing these groups, as defined hereinabove, may be optionally substituted by at least one other substituent. The term xe2x80x9coptionally substitutedxe2x80x9d is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents. Various groups may be unsubstituted or substituted (i.e., they are optionally substituted) as indicated.
If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence of the method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley and Sons, N.Y. (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound.
Particular embodiments of this invention comprise the compounds of Formulas II and III, wherein n is 2 or 1, respectively, depicted by the formula: 
wherein:
W is CH or N;
Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, provided that Raxe2x80x2 is not an amino-substituted alkyl group;
R4 and R6 are each independently H or a lower alkyl group;
R5 is H or an alkyl group;
R7 is a substituent having the formula: 
wherein:
R8 and R9 are each independently H or lower alkyl;
p is an integer of from 1 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)OR15, xe2x80x94C(S)NR15R16, xe2x80x94C(xe2x95x90NR15)R16, xe2x80x94C(xe2x95x90NR15)OR16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO (NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof of said compound.
More specifically, preferred embodiments of Formula VI of this invention comprise the compounds depicted by the formula: 
wherein Raxe2x80x2, R4, R5, R6, R7, Z and Z1 are as defined above; and the compounds depicted by the formula: 
wherein Raxe2x80x2, R4, R5, R6, R7, Z and Z1 are as defined above.
In particular, this invention comprises the compounds depicted by the formula: 
wherein:
R1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, where the alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R2 and R3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents;
or R1 together with R2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R4 and R6 are each independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents;
R5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
R7 is a moiety having the formula: 
wherein:
R8 and R9 are each each independently H or a lower alkyl group;
m is 0 or 1;
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)OR15, xe2x80x94C(S)NR15R16, xe2x80x94C(xe2x95x90NR15)R16, xe2x80x94C(xe2x95x90NR15)OR16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Another embodiment of this invention comprises the compounds depicted by the formula: 
wherein:
R1 is H, halo or an alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group, where the alkoxy, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R2 and R3 are each independently H, halo or an alkoxy or lower alkyl group, where the alkoxy or lower alkyl group is unsubstituted or substituted with one or more suitable substituents;
or R1 together with R2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents;
R4 and R6 are each independently H or lower alkyl, unsubstituted or substituted with one or more suitable substituents;
R5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
R7 is a moiety having the formula: 
wherein:
R8 and R9 are each independently H or a lower alkyl group;
m is 0 or 1, provided that when m is 0 and R1 together with R2 form an aryl ring, the aryl ring is unsubstituted (e.g., R1 together with R2 and the pyrrole to which they are bound do not form a substituted indole);
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15R16, xe2x80x94C(S)R15, xe2x80x94C(S)OR15, xe2x80x94C(S)NR15R16, xe2x80x94Cxe2x95x90NR15)R16, xe2x80x94C(xe2x95x90NR15)OR16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17) xe2x80x94PO(NR15R16)NR17R18), xe2x80x94C(O)NR15R16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
In another embodiment of the compounds of the above formulas,
A1 is CH or N;
A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Zxe2x80x2 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, aryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)NR15R16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16) xe2x80x94PO(NR15R16)(OR17) xe2x80x94PO(NR15R16)(NR17R18) xe2x80x94C(O)NR15NR16R17, C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, aryl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above. Preferably, in the compounds of Formulas IX and X, R1 may be selected from H and a lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group, where the lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl or isoxazoyl group is unsubstituted or substituted with one or more substituents selected from alkyl (but not as a substituent for alkyl), hydroxy, halo, haloalkyl, alkoxy, haloalkoxy and alkylenedioxy moiety. Exemplary R1 groups include, but are not limited to H, phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-chlorophenyl, 2-xcex1,xcex1,xcex1-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, and 2,3-benzo[d]dioxolyl. Preferably, in the compounds of Formulas IX and X, R2 and R3 maybe each independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, and lower alkoxyalkyl. R4 and R6 may be each independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.
Yet another preferred embodiment of this invention comprises the compounds depicted by the formula: 
wherein:
each Rz is H or a suitable substituent and nz is an integer from 1 to 4;
R7 is a moiety having the formula: 
wherein:
R8 and R9 are each independently H or a lower alkyl group;
p is an integer of from 1 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
A4 is N(R13), C(R10)(R11), or O, where R10 and R11 are each independently H or a lower alkyl group, and R13 is H or an alkyl, aryl or acyl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O; and
each R3, R4, R5, R6, Z and Z1 are as defined above.
Preferably, in the compounds of Formula XI, each Rz is independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl, and lower alkoxyalkyl. R3 may be independently selected from H, halo, alkoxy, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl and R4 and R6 may be each independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl.
Another preferred embodiment of this invention comprise the compounds of Formula IV, wherein n is 1, depicted by the formula: 
wherein:
Raxe2x80x2 is an alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, where the alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
R5 is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents,;
each R6 is independently H or a lower alkyl group, unsubstituted or substituted with one or more suitable substituents,;
R7 is a moiety having the formula: 
wherein:
R8 and R9 are each independently H or a lower alkyl group;
m is 0 or 1;
p is an integer of from 0 to 5;
A1 is CH or N;
when p is 1, 2, 3, 4, or 5, A2 is C(R10)(R11), N(R12), S, S(O), S(O)2, or O, and when p is 0, A2 is C(R10)(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) where each R10, R11 and R12 is independently H or a lower alkyl group;
each A3 present is independently C(R10)(R11), N(R12), S, S(O), S(O)2, or O, where each R10, R11 and R12 is independently H or a lower alkyl group;
when p is 1, 2, 3, 4, or 5, A4 is N(R13), C(R10)(R11), or O, and when p is 0, A4 is N(R13)(R14), C(R10)(R11)(R12), and O(R14), where each R10, R11 and R12 is independently H or a lower alkyl group, each R13 is H or an alkyl, aryl, or acyl group, and each R14 is H or an alkyl or aryl group;
provided that no more than two heteroatoms occur consecutively in the above-depicted ring formed by A1, (A2)m, (A3)p, A4, and Cxe2x95x90O, where each dotted line in the ring depicts a single bond when A2 is present and a hydrogen atom when A2 is absent; and
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)OR15, xe2x80x94C(S)NR15R16, xe2x80x94C(xe2x95x90NR15)R16, xe2x80x94C(xe2x95x90NR15)OR16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, C(S)NR15NR16R17, where R15, R16, R17 and R18 are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
In another embodiment of the compounds of the above formulas, Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, xe2x80x94C(O)R15, xe2x80x94CO2R15, xe2x80x94CN, xe2x80x94C(O)NR15R16, xe2x80x94C(O)NR15OR16, xe2x80x94C(S)R15, xe2x80x94C(S)NR15R16, xe2x80x94NO2, xe2x80x94SOR16, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94SO2(NR15)(OR16), xe2x80x94SONR15, xe2x80x94SO3R15, xe2x80x94PO(OR15)2, xe2x80x94PO(OR15)(OR16), xe2x80x94PO(NR15R16)(OR17), xe2x80x94PO(NR15R16)(NR17R18), xe2x80x94C(O)NR15NR16R17, xe2x80x94C(S)NR15NR16R17, where R15, R16, R17 and R18 are independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the R15, R16, R17 and R18, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which is unsubstituted or substituted with one or more suitable substituents, or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above.
Preferably, in the compounds of Formula XII, Raxe2x80x2 may be selected from H, lower alkyl, phenyl, naphthyl, pyridyl, quinoyl, isoquinoyl and isoxazoyl, each of which may be substituted by alkyl (but not as a substituent for alkyl), hydroxy, halo, haloalkyl, alkoxy, haloalkoxy and alkylenedioxy. Each R6 may be independently selected from H, unsubstituted lower alkyl, haloalkyl and loweralkoxyalkyl.
If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
If an inventive compound is an acid, a desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines, such as piperidine, morpholine, and piperazine; as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
All compounds of this invention contain at least one chiral center and may exist as single stereoisomers (e.g., single enantiomers or diastereomers), any mixture of stereosisomers (e.g., any mixture of enantiomers or diastereomers) or racemic mixtures thereof. All such single stereoisomers, mixtures and racemates are intended to be encompassed within the broad scope of the present invention. Where the stereochemistry of the chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral carbon. When used describe a particular compound, the term xe2x80x9coptically purexe2x80x9d is used herein to indicate that the compound is substantially enantiomerically or diastereomerically pure. Compounds that are substantially enatiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer. Compounds that are substantially diastereomerically pure contain at least 90% of a single isomer of each chiral carbon center present in the diastereomer, and preferably contain at least 95% of a single isomer of each chiral carbon. More preferably, when an optically active compound is desired, it contains at least 97.5% of a single isomer and, most preferably, at least 99% of the single isomer. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single isomer. The term xe2x80x9cracemicxe2x80x9d or xe2x80x9cracemic mixturexe2x80x9d refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and mixtures of enantiomeric diastereomers. The compounds of this invention may be obtained in stereochemically (e.g., enantiomerically or diastereomerically) pure or substantially stereochemically pure form. Such compounds may be obtained synthetically, according to the procedures described herein using optically pure or substantially optically pure materials. Alternatively, these compounds may be obtained by resolution/separation of a mixture of stereoisomers, including racemic mixtures, using conventional procedures. Exemplary methods that may be useful for the resolution/separation of stereoisomeric mixtures include chromatography and crystallization/re-crystallization. Other useful methods may be found in xe2x80x9cEnantiomers, Racemates, and Resolutions,xe2x80x9d J. Jacques et al., 1981, John Wiley and Sons, New York, N.Y. Preferred stereoisomers of the compounds of this invention are described herein.
In especially preferred embodiments of Formulas V, VI, VII, VIII, IX, X, XI and XII, R5 (or Rx or Ry in Formulas II, III and VI) is H or an unsubstituted alkyl group or an optionally substituted lower alkyl group, where these groups are comprised of a straight- or branched-chain saturated hydrocarbon group, a straight- or branched-chain substituted saturated hydrocarbon group, or group comprised of a straight- or branched-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety. When R5 or Rx/Ry is a substituted alkyl group, the point of attachment of R5 or Rx/Ry is via a saturated hydrocarbon moiety. When R5 or Rx/Ry is a substituted saturated hydrocarbon group, the saturated hydrocarbon group may be optionally substituted with a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, where each alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl moiety thereof may be optionally substituted. When R5 or Rx/Ry is comprised of a saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety, the saturated hydrocarbon moiety may be bound to an unsaturated hydrocarbon moiety containing one or more double-bonds or triple-bonds, the terminal positions of which may be substituted by the substituents described above, or may contain additional straight- or branched-chain saturated hydrocarbon moieties. Preferably, the unsaturated hydrocarbon moiety contains one double-bond or one triple-bond, the terminal position(s) of which may optionally contain a straight- or branched-chain saturated hydrocarbon moiety. Preferably, if the unsaturated hydrocarbon moiety contains a double-bond, both terminal positions of the double bond contain a straight- or branched-chain saturated hydrocarbon moiety. In especially preferred embodiments, R5 or Rx/Ry is H or a lower alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl group, or a group comprised of a straight-chain saturated hydrocarbon moiety and an unsaturated hydrocarbon moiety, where the alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents. Preferably, R5 or Rx/Ry is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, substituted or unsubstituted -methylthienyl or substituted or unsubstituted benzyl, where the methyl, ethyl, propyl, propenyl, butenyl or cyclohexyl moiety thereof is optionally substituted with one or more substituents independently selected from lower alkoxy, hydroxy, amino, alkylamino or dialkylamino and halogen, the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino or dialkylamino and halogen and the thienyl moiety of the substituted -methylthienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halogen. When R5 or Rx/Ry is substituted methyl, the methyl (methylene) moiety may be substituted with an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group. Most preferably, R5 or Rx/Ry is H, ethyl, 2-propyn-1-yl, -methylcyclohexyl, or substituted or unsubstituted benzyl, where the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy and halogen.
In the especially preferred embodiments of Formulas V, VI, VII, VIII, XI, X XI and XII, R5 (or Rx or Ry in Formulas II, III and VI) is selected from H and: 
wherein Rxe2x80x2 may be H or alkyl and each Rxe2x80x3 may be H or independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino or dialkylamino, and halogen. 
In especially preferred embodiments of Formulas V, VI, VII, VIII, IX, X, XI and XII, R7 (or Rc in Formulas I, II, III and VI) is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2. More preferably, R7 is 
Preferably, in each of the formulas described herein, Z and Z1 are each independently H, alkyl, where the alkyl is unsubstituted or substituted with one or more suitable substituents, xe2x80x94CO2R15 (in Formulas V to XII) or xe2x80x94CO2R1 (in Formulas I to VI), where R1 and R15 are as defined above, or Z and Z1, taken together with the atom to which they are attached, form a heterocycloalkyl group, as defined above, which may be optionally substituted. In one useful embodiment of the compounds of this invention, Z and/or Z1 may be xe2x80x94C(S)ORn or xe2x80x94C(S)OR19, where Rn and R19 are as defined above. Such compounds may be prepared using procedures described in K. Hartke, et al., Leibigs Ann. Chem., 321-330 (1989) and K. Hartke, et al., Synthesis, 960-961 (1985). More preferably, the heterocycloalkyl group may optionally contain O, N, S and/or P and may be substituted by one or more of oxo (keto) or thioketo. In another preferred embodiment of this invention, Z and Z1 are each independently selected from H, lower alkyl which is unsubstituted or substituted with one or more suitable substituents, xe2x80x94CO2H, xe2x80x94CO2-alkyl and xe2x80x94CO2-cycloalkyl, or taken together with the atom to which they are attached form a heterocycloalkyl group, which is optionally substituted with one or more of keto or thioketo. In other preferred embodiments of this invention, Z and Z1 are not both H. Most preferably, Z1 is H or lower alkyl and Z is a xe2x80x94CO2H, xe2x80x94CO2-alkyl, xe2x80x94CO2-alkylaryl, xe2x80x94CO2-alkylheteroaryl, xe2x80x94CO2-cycloalkyl group, where the lower alkyl, -alkyl, -cycloalkyl, -alkylaryl and -alkylheteroaryl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z1 and Z taken together with the atom to which they are attached form a heterocycloalkyl group, which may be optionally substituted. Exemplary Z groups include, but are not limited to: substituted and unsubstituted xe2x80x94CO2-alkyl groups, which include straight- and branched-chain alkyl groups such as ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl and (2,2-dimethylpropyl)-oxycarbonyl, where the ethoxy, t-butoxy, isopropoxy, and (2,2-dimethylpropyl)-oxy moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted straight and branched-chain arylalkyl and heteroarylalkyl groups, such as benzyloxycarbonyl and pyridylmethyleneoxycarbonyl, where the benzyl and pyridylmethylene moieties thereof are unsubstituted or substituted with one or more suitable substituents; and include substituted and unsubstituted xe2x80x94CO2-cycloalkyl groups such as cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl groups, where the cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl moieties thereof are unsubstituted or substituted with one or more suitable substituents, or Z1 and Z taken together with the atom to which they are attached form 
In another embodiment of this invention, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
In yet another embodiment of this invention, Z1 is H and Z is selected from ethoxycarbonyl, t-butoxycarbonyl, isopropoxycarbonyl, (2,2-dimethylpropyl)-oxycarbonyl, benzyloxycarbonyl, pyridylmethyleneoxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and cycloheptyloxycarbonyl, or Z1 and Z taken together with the atom to which they are attached form 
In the compounds of each of the above-described Formulas, Rc and R7 are defined to provide structures where m is 1 and p is 1-5 (i.e., both A2 and A3 are present), m is 0 and p is 0 (i.e., both A2 and A3 are absent), m is 0 and p is 1-5 (i.e., A2 is absent and A3 is present) and m is 1 and p is 0 (i.e., A2 is present and A3 is absent). Accordingly, one of ordinary skill in the are will recognize that when both A2 and A3 are present (m is 1 and p is 1-5), the dotted line between A1 and A2 represents a bond and the dotted line between A2 and A3 represents a bond and when both A2 and A3 are absent (m is 0 and p is 0); A2, A3 and the dotted line between these substituents are not present), the remaining dotted line in the structure between A1 and A2 represents a hydrogen (e.g., A1 is CH2 or NH). In embodiments of this invention when A2 is absent and A3 is present (m is 0 and p is 1-5), the dotted line between A1 and A2 represents a hydrogen and the dotted line between A2 and A3 represents a hydrogen (e.g., A1 is CH2 or NH and A3 is CH(Rg)(Rh), NH(Ri), SH, S(O)H, S(O)2H, or OH or CH(R10)(R11), NH(R12), SH, S(O)H, S(O)2H, or OH); and when A2 is present and A3 is absent (m is 1 and p is 0), the dotted line between A1 and A2 represents a bond and A2 is C(Rg)(Rh)(Ri), N(Rg)(Ri), S(Rg), S(O)(Rg), S(O)2(Rg), or O(Rg) or A2 is C(R10))(R11)(R12), N(R10)(R12), S(R10), S(O)(R10), S(O)2(R10), or O(R10) or the dotted line between A2 and A3 represents a hydrogen and A2 is CH(Rg)(Rh), NH(Ri), SH, S(O)H, S(O)2H, or OH or A2 is CH(R10)(R11), NH(R12), SH, S(O)H, S(O)2H, or OH. In preferred embodiments of the compounds of each of the above-described Formulas, m is 1 and p is 1 or 2 or m is 0 and p is 0 or m is 1 and p is 0. More preferably, when m is 1 and p is 1 or 2, A2 and A3 are both C(Rg(Rh) or C(R10)(R11), respectively. More preferably, m is 1 and p is 1.
In the compounds of Formulas I to IV, Rd and each Rb are preferably H, in the compounds of Formulas V to XI, each R4 and R6 are preferably H and in the compounds of Formula XIII, each R6 is preferably H.
Other embodiments of this invention comprise compounds having the formula: 
wherein:
Ra is (C1-C4)alkylcarbonyl-(C1-C4)alkyl, (C3-C8)cycloalkylcarbonyl-(C1-C4)alkyl, arylcarbonyl-(C1-C4)alkyl, heteroarylcarbonyl-(C1-C4)alkyl, (C1-C4)alkylcarbonylamino-(C1-C4)alkyl, (C3-C8) cycloalkylcarbonylamino-(C1-C4)alkyl, heterocycloalkylcarbonylamino-(C1-C4)alkyl, arylcarbonylamino-(C1-C4)alkyl, heteroarylcarbonylamino-(C1-C4)alkyl, (C1-C4 alkylaminocarbonyl-(C1-C4)alkyl, (C3-C8)cycloalkylaminocarbonyl-(C1-C4)alkyl, heterocycloalkylaminocarbonyl-(C1-C4)alkyl, arylaminocarbonyl-(C1-C4)alkyl, heteroarylaminocarbonyl-(C1-C4)alkyl, wherein each (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents; preferably Ra is (C1-C4)alkylcarbonyl-(C1-C4)alkyl, (C5-C6)cycloalkylcarbonyl-(C1-C4)alkyl, arylcarbonyl-(C1-C4)alkyl, heteroarylcarbonyl-(C1-C4)alkyl, (C1-C4)alkylcarbonylamino-(C1-C4)alkyl, C3-C4 cycloalkylcarbonylamino-(C1-C4)alkyl, heterocycloalkylcarbonylamino-(C1-C4)alkyl, arylcarbonylamino-(C1-C4)alkyl, heteroarylcarbonylamino-(C1-C4)alkyl, (C1-C4alkylaminocarbonyl-(C1-C4)alkyl, (C5-C6)cycloalkylaminocarbonyl-(C1-C4)alkyl, heterocycloalkylaminocarbonyl-(C1-C4)alkyl, arylaminocarbonyl-(C1-C4)alkyl, heteroarylaminocarbonyl-(C1-C4)alkyl, wherein each (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents; more preferably, Ra is (C1-C4)alkylcarbonyl-(C1-C4)alkyl, phenylcarbonyl-(C1-C4)alkyl, naphthylcarbonyl-(C1-C4)alkyl, pyrrolylcarbonyl-(C1-C4)alkyl, indolylcarbonyl-(C1-C4)alkyl, (C1-C4)alkylcarbonylamino-(C1-C4)alkyl, pyrrolylcarbonylamino-(C1-C4)alkyl, indolylcarbonylamino-(C1-C4)alkyl, phenylcarbonylamino-(C1-C4)alkyl, naphthylcarbonylamino-(C1-C4)alkyl, (C1-C4)alkylaminocarbonyl-(C1-C4)alkyl, pyrrolylaminocarbonyl-(C1-C4)alkyl, phenylaminocarbonyl-(C1-C4)alkyl, naphthylaminocarbonyl-(C1-C4)alkyl, wherein each (C1-C4)alkyl, phenyl, naphthyl, pyrrolyl, and indolyl moiety thereof is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; and preferably, where said indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl and C1-C4 haloalkyl;
Rb and Rd are each independently H or C1-C4 alkyl; preferably Rb and Rd are each H;
Rc is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl;
xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2;
preferably Rc is xe2x80x94CH2CH2C(O)NH2 or 
where n is 1; more
preferably, Rc is xe2x80x94CH2CH2C(O)NH2 or 
xe2x80x83and
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
more preferably Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
provided that Rc is 
where n is 1 or 2, when Ra is an indolylcarbonylamino-(C1-C4)alkyl group where the indolyl moiety thereof is substituted with one or more suitable substituents or Ra is is not an amino-substituted (C1-C4)alkylcarbonylamino-(C1-C4)alkyl or Ra is is not an amino-substituted (C1-C4)alkylcarbonyl-(C1-C4)alkyl; and Rc is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2, when
Ra is an indolylcarbonylamino-(C1-C4)alkyl group where the indolyl moiety thereof is unsubstituted or Ra is a (C1-C4) alkylaminocarbonyl-(C1-C4)alkyl, (C3-C8)cycloalkylaminocarbonyl-(C1-C4)alkyl, heterocycloalkylaminocarbonyl-(C1-C4)alkyl, arylaminocarbonyl-(C1-C4)alkyl, heteroarylaminocarbonyl-(C1-C4)alkyl, or heteroarylcarbonylamino-(C1-C4)alkyl group, wherein each (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof is unsubstituted or substituted with one or more suitable substituents;
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Preferably, in the compounds of Formula I, as defined above, R2 is 
where n is 1, when
Ra is an indolylcarbonylamino-(C1-C4)alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl and C1-C4 haloalkyl, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; and Rc is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1, when
Ra is (C1-C4)alkylcarbonyl-(C1-C4)alkyl, (C5-C6)cycloalkyl carbonyl-(C1-C4)alkyl, arylcarbonyl-(C1-C4)alkyl, heteroarylcarbonyl-(C1-C4)alkyl, (C1-C4)alkylcarbonylamino-(C1-C4)alkyl, C3xe2x80x94C8 cycloalkylcarbonylamino-(C1-C4)alkyl, heterocycloalkylcarbonylamino-(C1-C4)alkyl, arylcarbonylamino-(C1-C4)alkyl, heteroarylcarbonylamino-(C1-C4)alkyl, (C1-C4alkylaminocarbonyl-(C1-C4)alkyl, (C3-C8)cycloalkylaminocarbonyl-(C1-C4)alkyl, heterocycloalkylaminocarbonyl-(C1-C4)alkyl, arylaminocarbonyl-(C1-C4)alkyl, heteroarylaminocarbonyl-(C1-C4)alkyl, wherein each (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl moiety thereof unsubstituted or substituted with one or more suitable substituents.
More preferably, in the compounds of Formula I, as defined above, Rc is 
when Ra is an indolylcarbonylamino-(C1-C4)alkyl group where the indolyl moiety thereof is substituted with one or two substituents independently selected from halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl and C1-C4 haloalkyl; and
and Rc is xe2x80x94CH2CH2C(O)NH2 or 
when Ra is (C1-C4)alkylcarbonyl-(C1-C4)alkyl, phenylcarbonyl-(C1-C4)alkyl, naphthylcarbonyl-(C1-C4)alkyl, pyrrolylcarbonyl-(C1-C4)alkyl, indolylcarbonyl-(C1-C4)alkyl, (C1-C4)alkylcarbonylamino-(C1-C4)alkyl, pyrrolylcarbonylamino-(C1-C4)alkyl, indolylcarbonylamino-(C1-C4)alkyl, phenylcarbonylamino-(C1-C4)alkyl, naphthylcarbonylamino-(C1-C4)alkyl, (C1-C4)alkylaminocarbonyl-(C1-C4)alkyl, phenylaminocarbonyl-(C1-C4)alkyl, naphthylaminocarbonyl-(C1-C4)alkyl, wherein each (C1-C4)alkyl, phenyl, naphthyl and pyrrolyl moiety thereof is group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; and said indolyl moiety is unsubstituted.
Other specific compounds of this invention have the formula: 
Raxe2x80x2 is a (C1-C4)alkyl, (C3-C8)cycloalkyl, aryl or heteroaryl group, wherein the (C1-C4)alkyl, (C3-C8)cycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from (C1-C4)alkyl, aryl, (C3-C8)cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, (C1-C4)alkoxy, alkylenedioxy (as a substituent for aryl or heteroaryl), aryloxy, (C3-C8)cycloalkoxy, heteroaryloxy, and carboxyl where the (C1-C4)alkyl, aryl, (C3-C8)cycloalkyl, heterocycloalkyl, heteroaryl moieties thereof are optionally substituted by one or more of (C1-C4)alkyl (except for alkyl), halo, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, alkylenedioxy, aryl or heteroaryl, where the aryl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy, nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups; preferably, Raxe2x80x2 is a (C1-C4)alkyl, pyrrolyl, indolyl, phenyl or naphthyl group, where the (C1-C4)alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkoxy or C1-C4 haloalkoxy and the pyrrolyl, indolyl, phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, Raxe2x80x2 is an unsubstituted (C1-C4)alkyl, or a pyrrolyl, indolyl, phenyl or naphthyl group, where the pyrrolyl, indolyl, phenyl or naphthyl group is unsubstituted or substituted by one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; in specific embodiments, Raxe2x80x2 is an unsubstituted (C1-C4)alkyl, pyrrolyl, indolyl, phenyl or naphthyl group or a pyrrolyl group substituted by phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-chlorophenyl, 2-xcex1,xcex1,xcex1-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl or an indolyl group substituted by halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxyalkyl;
n is 1, 2 or 3; preferably n is 1 or 2; more preferably, n is 2;
Rx is H and Ry is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, Rx is H and Ry is substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, Rx is H and Ry is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, where Rx is H and Ry is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;
Rc is 
where n is 1 or 2; preferably Rc is 
xe2x80x83and
Rb, Rd, Z and Z1 are defined as in Formula I, above.
Yet other specific compounds of this invention have the formula: 
wherein:
Raxe2x80x2 is a (C1-C4)alkyl, (C3-C8)cycloalkyl, aryl or heteroaryl group, wherein the (C1-C4)alkyl, (C3-C8)cycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents provided that Raxe2x80x2 is not an amino-substituted (C1-C4)alkyl group; preferably, Raxe2x80x2 is a (C1-C4)alkyl, phenyl, naphthyl, pyrrolyl or indolyl group, where the (C1-C4)alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkoxy or C1-C4 haloalkoxy and the phenyl, naphthyl, pyrrolyl or indolyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl or heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, Raxe2x80x2 is a pyrrolyl or indolyl group, where the pyrrolyl or indolyl group is unsubstituted or substituted by one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; even more preferably, Raxe2x80x2 is a pyrrolyl group that is unsubstituted or substituted by phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-chlorophenyl, 2-xcex1,xcex1,xcex1-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;
n is 1, 2 or 3; preferably n is 1;
Rx is H and Ry is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, Rx is H and Ry is substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, Rx is H and Ry is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, where Rx is H and Ry is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl; 
Rb, Rd, Z and Z1 are defined as in Formula I, above.
Another embodiment of this invention comprises compounds having the formula: 
wherein:
Raxe2x80x2 is a (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, wherein the (C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, aryl and heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, Raxe2x80x2 is a (C1-C4)alkyl, phenyl or naphthyl group, where the (C1-C4)alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkoxy or C1-C4 haloalkoxy and the phenyl or naphthyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy and phenyl, where the phenyl is unsubstituted or substituted by one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; in specific embodiments, Raxe2x80x2 is a halo-substituted phenyl group;
n is 1, 2 or 3; preferably, n is 1 or 2; more preferably, n is 1;
Rx is H and Ry is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, Rx is H and Ry is substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, Rx is H and Ry is ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, where Rx is H and Ry is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl; and
and Rb, Rc, Rd, Z and Z1 are defined as in Formula I, above.
Other specific embodiments of this invention comprise the compounds having the formula: 
wherein:
W is CH or N;
Raxe2x80x2 is a C1-C4 alkyl, C3-C8 cycloalkyl, aryl or heteroaryl group, where the C1-C4 alkyl, C3-C8 cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, provided that Raxe2x80x2 is not an amino-substituted alkyl group; preferably, Raxe2x80x2 is a C1-C4 alkyl, C5-C6 cycloalkyl, phenyl, naphthyl or heteroaryl group, where the phenyl, naphthyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy, aryl, heterocycloalkyl, and heteroaryl, where the aryl, heterocycloalkyl and heteroaryl is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, Raxe2x80x2 is a C1-C4 alkyl, C5-C6 cycloalkyl, phenyl, naphthyl, pyrrolyl or indolyl, group, where the phenyl, naphthyl, pyrrolyl or indolyl, group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, methylenedioxy and a phenyl, naphthyl, isoquinoyl, pyridyl or isoxazolyl group, wherein the phenyl, naphthyl, isoquinoyl, pyridyl and isoxazolyl group is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy;
R4 and R6 are each independently H or C1-C4 alkyl; preferably R4 and R6 are each H;
R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, R5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, R5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl; 
and
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
most preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Specific embodiments of Formula VI of this invention comprise the compounds depicted by the formula: 
and the compounds depicted by the formula: 
wherein Raxe2x80x2, R4, R5, R6, R7, Z and Z1 are as defined above.
In addition, specific embodiments of this invention comprise the compounds depicted by the formula: 
wherein:
R1 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, R1 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, R1 is H, phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-chlorophenyl, 2-xcex1,xcex1,xcex1-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;
R2 and R3 are each independently H or C1-C4 alkyl; preferably R2 and R3 are each H; or
R1 together with R2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents; or preferably, R1 together with R2 form a phenyl ring, which is unsubstituted or substituted with one or more suitable substituents and R3 is H;
R4 and R6 are each independently H or C1-C4 alkyl; preferably R4 and R6 are each H;
R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, R5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, R5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;
R7 is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl;
xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2;
preferably, R7 is xe2x80x94CH2CH2C(O)NH2 or 
where n is 1;
most preferably, R7 is xe2x80x94CH2CH2C(O)NH2 or 
xe2x80x83and
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
most preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Another specific embodiment of this invention comprises the compounds depicted by the formula: 
wherein:
R1 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl, or an aryl or heteroaryl group, where the aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents; preferably, R1 is H, halo, C1-C4 alkyl, C1-C4 haloalkyl or a phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group, where the phenyl, naphthyl, isoxazolyl, pyridyl, quinoyl or isoquinoyl group is unsubstituted or substituted with one or more substituents independently selected from: halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, R1 is H, phenyl, xcex1-naphthyl, xcex2-naphthyl, 2-chlorophenyl, 2-xcex1,xcex1,xcex1-trifluoromethylphenyl, 3-chloro-6-methoxyphenyl, 2,3-dichlorophenyl, 4-isoquinoyl, 3-iso-propylphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl, 2-methylphenyl (o-tolyl), 2-bromophenyl, 3-pyridyl, 4-pyridyl, 3-methyl-isoxazol-5-yl, 3,3,3-trifluoroprop-1-yl, or 2,3-benzo[d]dioxolyl;
R2 and R3 are each independently H or C1-C4 alkyl; preferably R2 and R3 are each H; or
R1 together with R2 form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring, where the cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is unsubstituted or substituted with one or more suitable substituents; or preferably, R1 together with R2 form an unsubstituted phenyl ring and R3 is H;
R4 and R6 are each independently H or C1-C4 alkyl; preferably R4 and R6 are each H;
R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1 -yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, R5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, R5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;
R7 is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; xe2x80x94CH2NHC(O)CH3; and 
where n is 1 or 2;
preferably, R7 is xe2x80x94CH2CH2C(O)NH2 or , 
where n is 1;
most preferably, R7 is xe2x80x94CH2CH2C(O)NH2 or 
provided that when R1 together with R2 form a phenyl ring and the phenyl ring is substituted, R7 is selected from 
where n is 1 or 2,
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
most preferably, Z1 is H and
Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Yet another specific embodiment of this invention comprises the compounds depicted by the formula: 
wherein:
each Rz is independently selected from halo and a C1-C4 alkoxy, C1-C4 alkyl, aryl, heterocycloalkyl or heteroaryl group where the C1-C4 alkoxy or C1-C4 alkyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkoxy or C1-C4 haloalkoxy and the aryl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted by one ore more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy and nz is an integer from 1 to 4; preferably, each Rz is independently selected from halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxyalkyl and nz is an integer from 1 to 2; more preferably, each Rz is independently selected from halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl and C1-C4 haloalkyl, and nz is 1 or 2;
R3 is H, halo, C1-C4 alkoxy, unsubstituted C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxyalkyl; preferably, R3 is H or C1-C4 alkyl; more preferably, R3 is H;
R4 and each R6 are independently selected from H, unsubstituted lower alkyl, haloalkyl and lower alkoxyalkyl, preferably, R4 and each R6 are independently H or C1-C4 alkyl; more preferably R4 and R6 are each H;
R5 is H, C1-C4 alkyl C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, R5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, R5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl; 
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
most preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Another preferred embodiment of this invention comprises the compounds of Formula XII, depicted by the formula: 
wherein:
Raxe2x80x2 is a C1-C4 alkyl, aryl, C3-C7 cycloalkyl, heterocycloalkyl or heteroaryl group, where the C1-C4 alkyl, aryl, C3-C7 cycloalkyl, heterocycloalkyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, alkylenedioxy (as a substituent for aryl or heteroaryl), nitro, amino, hydroxamino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio, aryl or heteroaryl, where the aryl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; preferably, Raxe2x80x2 is a C1-C4 alkyl, C1-C4 haloalkyl, phenyl, naphthyl, C5-C6 cycloalkyl, isoquinoyl, pyridyl or pyrrolyl group, where the phenyl, naphthyl, isoquinoyl, pyridyl or pyrrolyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and methylenedioxy; more preferably, Raxe2x80x2 is a phenyl group, where the phenyl group is unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;
each R6 is independently H or C1-C4 alkyl; preferably, each R6 is H;
R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or an arylalkyl, heteroarylalkyl, cycloalkylalkyl group or a straight-chain saturated hydrocarbon moiety or an unsaturated hydrocarbon moiety, where the arylalkyl, heteroarylalkyl, cycloalkylalkyl group is unsubstituted or substituted with one or more suitable substituents; preferably, R5 is H or substituted or unsubstituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, -methylthienyl or benzyl, where the substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, and -methylcyclohexyl is substituted by one or more substituents independently selected from halo, alkoxy, aryloxy, alkylthio and arylthio; the subsituted thienyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, hydroxy, amino, alkylamino, dialkylamino and halo; and the phenyl moiety of the substituted benzyl is substituted by one or more substituents independently selected from lower alkyl, lower alkoxy, alkylenedioxy, hydroxy, amino, alkylamino, dialkylamino and halo; more preferably, R5 is H, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, 2-propen-1-yl, 2-propen-2-yl, 2-propyn-1-yl, 3-methyl-3-buten-1-yl, -methylcyclohexyl, benzyl or substituted benzyl, wherein the phenyl moiety of the substituted benzyl comprises one or more substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy and halo; even more preferably, R5 is H, ethyl, 2-propyn-1-yl, methylcyclohexyl or benzyl;
R7 is selected from xe2x80x94CH2CH2C(O)NH2; xe2x80x94CH2CH2C(O)NH-alkyl; 
Z1 is H or C1-C4 alkyl and Z is xe2x80x94CO2-alkyl, xe2x80x94CO2-cycloalkyl, xe2x80x94CO2-alkylaryl or xe2x80x94CO2-alkylheterocycloaryl, or Z1 and Z taken together with the atom to which they are attached form 
preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3, xe2x80x94CO2(CH(CH3)2), xe2x80x94CO2(C(CH3)3), xe2x80x94CO2CH2(C(CH3)3), xe2x80x94CO2(cyclo-C5H9) or Z1 and Z taken together with the atom to which they are attached form 
most preferably, Z1 is H and Z is xe2x80x94CO2CH2CH3 or Z1 and Z taken together with the atom to which they are attached form 
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate of said compound.
Preferred embodiments of this invention comprise the compounds depicted by the formula: 
wherein Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where said alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each W, R4, R5, R6, R7, Z and Z1 are as defined in VI above, provided that Raxe2x80x2 is not amino-substituted alkyl.
Particularly preferred embodiments of the compounds of Formula VI-a comprise the compounds depicted by the formula: 
wherein Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where said alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R4, R5, R6, R7, Z and Z1 are as defined above, provided that Raxe2x80x2 is not amino-substituted alkyl.
Other preferred embodiments of the compounds of Formula VI-a comprise the compounds depicted by the formula: 
wherein Raxe2x80x2 is an alkyl, cycloalkyl, aryl or heteroaryl group, where said alkyl, cycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R4, R5, R6, R7, Z and Z1 are as defined above, provided that Raxe2x80x2 is not amino-substituted alkyl.
More preferably, the compounds of this invention have the formula: 
wherein R1 is an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is unsubstituted or substituted with one or more suitable substituents, and each R2, R3, R4, R5, R6, R7, Z and Z1 are as defined above for IX.
In another preferred embodiment, the compounds of this invention have the formula: 
wherein each R1, R2, R3, R4, R5, R6, R7, Z and Z1 are as defined above.
Yet another preferred embodiment of this invention comprises the compounds depicted by the formula: 
wherein each R2, R3, R4, R5, R6, Z and Z1 are as defined above and R7 is a moiety having the formula: 
wherein each R8, R9, A1, A2, A3, A4 and p are as defined above.
Another particularly preferred embodiment of this invention comprises the compounds depicted by the formula: 
wherein each Raxe2x80x2, R5, R6, R7, Z and Z1 are as defined above. More preferably, R5 is H and the invention comprises the compounds depicted by the formula: 
wherein each Raxe2x80x2, R6, R7, Z and Z1 are as defined above.
In the compounds of Formulas VI-a to XII-b, R6 is preferably H. In the compounds of Formulas VI-a to XI-a, each R4 and R6 is preferably H.
Preferred specific compounds include those of any of the Examples below, especially: 
Preferred specific embodiments of the compounds of this invention include any one of the following: 
The invention is also directed to intermediate compounds of Formula XIII which are useful in the synthesis of certain compounds of Formulas I-XII: 
wherein R5xe2x80x2 is a lower alkyl or aryl group, where the lower alkyl or aryl group is unsubstituted or substituted with one or more suitable substituents, (where xe2x80x94CH2-R5xe2x80x2 represents R5 as defined above) and RE is H or an alkyl or aryl group, where the alkyl or aryl group is unsubstituted or substituted with one or more suitable substituents.
The invention is also directed to pharmaceutically acceptable salts of the compounds of Formulas XIII. Preferred examples of the compounds of Formula XIII, include the following: 
and pharmaceutically acceptable salts thereof. Exemplary preferred RE groups include, but are not limited to, H, methyl, tert-butyl, allyl, and benzyl, as illustrated in the following: 
The antipicornaviral compounds of this invention include prodrugs, the pharmaceutically active metabolites, and the pharmaceutically acceptable salts and solvates thereof. In preferred embodiments, the compounds of Formulas I to XII, prodrugs, pharmaceutically acceptable salts, and pharmaceutically active metabolites and solvates thereof have an antipicornaviral activity, more preferably antirhinoviral activity, corresponding to an EC50 less than or equal to 100 xcexcM in the H1-HeLa cell culture assay.
A xe2x80x9cprodrugxe2x80x9d is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active. A prodrug may be a derivative of one of the compounds of this invention that contains a moiety, such as for example xe2x80x94CO2R, xe2x80x94PO(OR)2 or xe2x80x94Cxe2x95x90NR, that may be cleaved under physiological conditions or by solvolysis. Any suitable R substituent may be used that provides a pharmaceutically acceptable solvolysis or cleavage product. A prodrug containing such a moiety may be prepared according to conventional procedures by treatment of a compound of this invention containing, for example, an amido, carboxylic acid, or hydroxyl moiety with a suitable reagent. A xe2x80x9cpharmaceutically active metabolitexe2x80x9d is intended to mean a pharmacologically active compound produced through metabolism in the body of a specified compound. Prodrugs and active metabolites of compounds of this invention of the above-described Formulas may be determined using techniques known in the art, for example, through metabolic studies. See, e.g., xe2x80x9cDesign of Prodrugs,xe2x80x9d (Bundgaard, ed.), 1985, Elsevier Publishers B. V., Amsterdam, The Netherlands. A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, xcex3-hydroxybutyrates, glycollates, tartrates, methane-sulfonates (mesylates), propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A xe2x80x9csolvatexe2x80x9d is intended to mean a pharmaceutically acceptable solvate form of a specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope of the present invention and specified formulas.
The present invention is also directed to a method of inhibiting picornaviral 3C protease activity, comprising contacting the protease with an effective amount of a compound of Formulas I to XII, or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. For example, picornaviral 3C protease activity may be inhibited in mammalian tissue by administering a compound of Formulas I to XII or a pharmaceutically acceptable salt, prodrug, pharmaceutically active metabolite, or solvate thereof. More preferably, the present method is directed at inhibiting rhinoviral protease activity. xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, including, but not limited to human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, meningitis virus, and hepatitis A virus. The methods of treatment for mitigation of a disease condition include the use of the compounds in this invention in any conventionally acceptable manner, for example, as a prophylactic. The activity of the inventive compounds as inhibitors of picornaviral 3C protease activity may be measured by any of the suitable methods known to those skilled in the art, including in vivo and in vitro assays. An example of a suitable assay for activity measurements is the antiviral H1-HeLa cell culture assay described herein.
Administration of the compounds of the Formulas I to XII and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any of the generally accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, nasal, parenteral, topical, transdermal, and rectal.
An inventive compound of Formulas I to XII or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions of the invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use or mode of administration. In preferred embodiments, the inventive pharmaceutical compositions are delivered orally, or intranasally in the form of suspensions. Acceptable methods of preparing suitable pharmaceutical forms of the pharmaceutical compositions may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques of the pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration.
The compounds (active ingredients) may be formulated into solid oral dosage forms which may contain, but are not limited to, the following inactive ingredients: diluents (i.e., lactose, corn starch, microcrystalline cellulose), binders (i.e., povidone, hydroxypropyl methylcellulose), disintegrants (i.e., crospovidone, croscarmellose sodium), lubricants (i.e., magnesium stearate, stearic acid), and colorants (FDandC lakes or dyes). Alternatively, the compounds may be formulated into other oral dosage forms including liquids, suspensions, emulsions, or soft gelatin capsules, with each dosage form having a unique set of ingredients.
Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension. A dose of the pharmaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound of Formulas I to XII or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of picornaviral 3C protease activity, by any known or suitable method of administering the dose, including: topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository, parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A xe2x80x9ctherapeutically effective amountxe2x80x9d is intended to mean the amount of an inventive agent that, when administered to a mammal in need thereof, is sufficient to effect treatment for disease conditions alleviated by the inhibition of the activity of one or more picornaviral 3C proteases, such as human rhinoviruses, human poliovirus, human coxsackieviruses, encephalomyocarditis viruses, menigovirus, and hepatitis A virus. The amount of a given compound of the invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, which amount may be routinely determined by artisans.
Preferably, compounds of the general formulas are prepared by the methods of the present invention, including the General Methods below, where the R1, R4, R5, R6, Z and Z1 substituents present in the compounds illustrated in the General and Specific Methods are as defined above. Abbreviations used herein include: DCC (1,3-dicyclohexylcarbodiimide), HOBT (1-hydroxybenzotriazole hydrate), HATU (O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate), IBX (2-iodoxybenzoic acid), FMOC (9-fluorenylmethoxycarbonyl), Boc (t-butoxycarbonyl), DIEA (diisopropylethylamine), DMSO (dimethylsulfoxide), TMSOTf (trimethylsilyl trifluoromethanesulfonate), TFA (trifluoroacetic acid), LiHMDS (lithium bis(trimethylsilyl)amide). 
In General Method 1, a sidechain protected (P) compound 1 (Dragovich, et al., J. Med. Chem. 1998, 41, 2819), is coupled using standard peptide coupling methods, to another amino acid with a different protecting group (Pxe2x80x2) on the alpha-nitrogen, to give di-peptide compound 2. The Pxe2x80x2 protecting group is then selectively removed, and the resulting amine is coupled to a substituted pyrrole-2-carboxylic acid (prepared as described in General Methods 4, 5, and 6), or a suitably activated analog of this acid, such as an acid chloride, ester or amide (X1xe2x95x90OH, halo, etc.), to give 3. The sidechain-protecting group P is then removed to give 4. These compounds may also be made using solid phase synthetic techniques (Dragovich, et al., Bioorg. Med. Chem., 1999 7, 589), where protecting group P constitutes a linker (such as the Rink linker) attached to solid phase resin. 
In General Method 2, compound 5 (prepared by a method analogous to that described in Tian, et al., U.S. Provisional Patent Application No. 60/150,358, filed Aug. 24, 1999 (now U.S. patent application Ser. No. 09/643,864) and also Baldwin et al., J. Org. Chem., 1971, 36, 1441) is coupled to another amino acid with sidechain protecting group P to give 6. The protecting group of 6 is removed, and the liberated amine is coupled to a 5-substituted pyrrole-2- carboxylic acid (prepared as described in General Methods 4, 5, and 6) via a suitably activated analog of this acid, such as an acid chloride, ester or amide (X1xe2x95x90OH, halo, etc.), to give compound 7.
In General Method 3, compound 5 is coupled to carboxylic acids of the type 8 (prepared as described in General Methods 7 and 8), where Wxe2x95x90N or CH, to give compound 9.
In General Method 4, 2,5-disubstituted pyrroles are prepared by bromination of pyrrole-2-carboxylic acid ester 10, where R is an alkyl or aryl group, which is unsubstituted or substituted with one or more suitable substituents, to give 11, followed by a transition-metal mediated carbon-carbon bond forming reaction (for example, using Pd0 with an appropriate ligand such as triphenylphosine or triphenylarsine) with an organometallic species, R1M (for example, an organoboronic acid or an organotin compound) to give 12.
General Method 5 depicts another method used to make 2,5-disubstituted pyrroles, analogous to the method described by Kruse, et al., Heterocycles, 1987, 26, 3141. A carboxylic acid 13 is converted to a suitably activated species 14 (X2=a Weinreb amide (xe2x80x94N(OCH3)CH3), halo, etc.) then reacted with a nucleophilic organometallic compound containing a protected aldehyde to provide 15. The aldehyde is deprotected to give 16, then is condensed with an ammonia equivalent such as ammonium chloride, to provide pyrrole 17. This pyrrole is then reacted with a phosgene-type equivalent such as trichloroacetyl chloride (analogous to the method described by Bailey, et al., Org. Synth., 1971, 51, 100), to provide the 2,5-disubstituted pyrrole 18. (X1xe2x95x90OH, halo, etc.). 
General Method 6 shows an alternate method to make 2,5-disubstituted pyrroles. Aldehyde 19 is reacted with a nucleophilic organometallic compound containing a protected aldehyde to provide alcohol 20. The alcohol is then oxidized to ketone 15 using standard methodology such as a Swern oxidation. Ketone 15 is carried on to pyrrole 18 using the same method as shown in General Method 5.
General Method 7 depicts the preparation of a pyrrole containing the keto-methylene moiety, 27, analogous to the method described by Gonzalez-Muniz et. al. (Gonzalez-Muniz, et al., Tetrahedron, 1992, 48, 5191; Garcia-Lopez, et al., Tetrahedron Lett., 1988, 29, 1577; Garcia-Lopez, et al., Tetrahedron, 1988, 44, 5138). Carboxylic acid 21 is converted to a suitably reactive intermediate 22 such as a Weinreb amide, acid chloride or ester (X2xe2x95x90N(OCH3)CH3, halo, etc.) , then reacted with an organometallic reagent (R4M, such as methyllithium) to give pyrrole-acetone compound 23. This compound is then halogenated to give 24 (where X3=halo), then reacted with a malonate salt (Rxe2x80x2=alkyl) to give 25. This compound is deprotonated by treatment with a strong base, then reacted with an electrophile (R5xe2x80x94X3) to give 26. Decarboxylation of compound 26 gives product 27.
General Method 8 shows the preparation of an optically active pyrrole containing the keto-methylene moiety, compound 33. Carboxylic acid 28 is converted to chiral amide 29, by coupling to a chiral amine or oxazolidinone, Nc, that is known to control enolate alkylation diastereoselectivity. Compound 29 is deprotonated, then reacted with an electrophile such as t-butyl bromoacetate, analogous to the method described by Charlton, et al., Can. J. Chem. 1997, 75, 1076, to give 30. The chiral auxiliary is removed, and the resulting acid is esterified to give 31. The Rxe2x80x2 ester of 31 is selectively removed, and the resulting acid is converted to the disubstituted amide 32, by coupling to a secondary amine. Compound 32 is reacted with pyrrole 17, under typical Vilsmeier reaction conditions (Silverstein, et al., Org. Synth., 1963, Coll. Vol. IV, 831) to give pyrrole 33. As used herein, Rxe2x80x2, Rxe2x80x2 and Rxe2x80x2xe2x80x3 are each independently lower alkyl, which is unsubstituted or substituted with one or more suitable substituents. 
In General Method 9, a pyrrole-carboxylic acid 34 (commercially available or prepared by methods described in the chemical literature or as prepared as described in General Methods 4, 5 and 6), where R1 is as defined above, is transformed into ketoester 35. Compound 35 is subsequently deprotonated and coupled with triflate 37 (which incorporates R5 and which can be prepared from hydroxy-ester 36, where Rxe2x80x3xe2x80x3 is alkyl or cycloalkyl, e.g., lower alkyl, allyl, benzyl, or C3-C6 cycloalkyl, which are unsubstituted or substituted with one or more suitable substituents) to afford intermediate 38 after acid-effected decarboxylation. Intermediate38 is related to compound 32 (General Method 8) and may be utilized in any of the previously described general syntheses where appropriate. Note that the NH present in pyrrole-carboxylic acid 34 may also be protected with a suitable protecting group which may be removed at any time during the synthesis of 38. The methodology for converting pyrrole-carboxylic acid 34 to intermediate 38 is generally described in: Hoffman, R. V.; Tao, J. Tetrahedron 1997, 53, 7119-7126.
In General Method 10, an amino acid 39 (or salt thereof) which incorporates R5 is transformed into hydroxy acid 40. This intermediate is subsequently converted to hydroxy ester 41 which may be utilized in General Method 9 above for the preparation of the compounds described in this invention.

Specific Method 1 describes the preparation of compounds containing a glutamine residue in the P-1 position. FMOC-4-amino-hept-2(trans)-enedioic acid-1 ethyl ester 42 (Dragovich, et al., J. Med. Chem. 1998, 41, 2819) was coupled to Rink polystyrene utilizing HATU as a coupling reagent to get 43. The FMOC protecting group was removed with piperidine, and the liberated amine was then coupled to an FMOC-protected amino acid 44 to get compound 45. The FMOC of 45 was again removed with piperidine, and the free amine was acylated with a 5-substituted-2-pyrrole carboxylic acid chloride 46 (prepared as described in Specific Methods 4,5, and 6). The final compound, 37, was cleaved from the resin with trifluoroacetic acid, to give compound 48.
Specific Method 2 describes the synthesis of compounds containing the oxo-pyrrolidine sidechain in the P-1 position. Boc-protected 4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl ester 49 (prepared by a method analogous to that described in Tian, et al., U.S. Provisional Patent Application No. 60/150,358, filed Aug. 24, 1999 and also Baldwin et al., J. Org. Chem., 1971, 36, 1441) was deprotected with HCl, then coupled using HATU to a Boc-protected amino acid 50. The Boc-protected product 51 was treated with HCl, then coupled to a 5-substituted-pyrrole-2-carboxylic acid chloride 46 (prepared as described in Specific Methods 4, 5, and 6), to produce product 52.
Specific Method 3 describes the preparation of compounds containing the pyrrole-ketomethylene moiety. Boc-protected 4S-amino-5-(2-oxo-pyrrolidin-3S-yl)-pent-2(trans)-enoic acid ethyl ester 49 was deprotected with HCl, then coupled to acid 53 (prepared as described in Specific Method 7 and 8), using HATU, to provide compound 54. 
Specific Method 4 describes the synthesis of 5-substituted-pyrrole-2-carboxylic acid chlorides. Pyrrole-2-carboxylic acid 55 was esterified with diazomethane, to give methyl ester 56, then brominated with N-bromosuccinimide to give 5-bromopyrrole 57. The bromide was reacted with a boronic acid using standard Suzuki coupling conditions to give 58. The methyl ester was cleaved with lithium hydroxide, and the resulting acid was converted to the acid chloride 46 using oxalyl chloride. 
Specific Method 5 describes an alternate method of pyrrole synthesis. Carboxylic acid 59 was converted to an acid chloride using oxalyl chloride, then converted to the N-methoxy-N-methyl amide with O,N-dimethyl hydroxylamine. This amide 60 was reacted with Grignard reagent 61 to give ketone 62. The dioxolane-protecting group was converted to the corresponding aldehyde with aqueous HCl, then condensed with ammonium chloride to give pyrrole 63. This pyrrole was reacted with trichloroacetyl chloride to give the disubstituted pyrrole 64, which was then hydrodrolyzed to the corresponding carboxylic acid with lithium hydroxide, then converted to the acid chloride 46 using oxalyl chloride. 
Specific Method 6 describes an alternate method of pyrrole synthesis. Aldehyde 65 was reacted with Grignard reagent 61 to give alcohol 66. This alcohol was subjected to Swern oxidation conditions to provide ketone 62, which was converted to the acid chloride 46 according to Specific Method 5. 
Specific Method 7 describes the synthesis of a racemic pyrrole-ketomethylene compound. 5xe2x80x94Substituted-pyrrole-2-carboxylic acid 67 (prepared as described in Specific Methods 4, 5 and 6) was converted to the Weinreb amide 68 using standard conditions, then treated with methyllithium to give pyrrole-acetone 69. This ketone was converted to its silyl-enol ether with trimethylsilyl triflate, then brominated with N-bromosuccinimide to give bromide 70. The bromide was displaced with sodium diethylmalonate to give malonate 71. The sodium enolate of this compound was alkylated to give 72, which was then de-esterified and de-carboxylated to give carboxylic acid 53. 
Specific Method 8 describes the enantioselective preparation of a pyrrole-ketomethylene compound. Carboxylic acid 73 was converted to the chiral amide 74 using standard conditions, then converted to its lithium enolate and alkylated with t-butylbromoacetate to give 75. The chiral auxiliary was removed with lithium hydroperoxide, and the resulting acid was esterified with diazomethane to give ester 76. The t-butylester was selectively removed with trifluoroacetic acid, and the resulting acid was converted to dimethyl amide 77 by treatment of the acid chloride (formed using oxalyl chloride) with dimethylamine hydrochloride. Amide 77 was reacted with pyrrole 63 (prepared as described in Specific Methods 4, 5 and 6) using standard Vilsmeier conditions to give pyrrole-ketomethylene 78. The methyl ester was cleaved with lithium hydroxide to give carboxylic acid 79. 
In Specific Method 9, H-D-propargyl glycine (80) (or a suitable salt thereof) is treated with sodium nitrite under mildly acidic aqueous conditions to provide hydroxy acid 81 in good yield. This material is esterified by exposure to acidic methanol to give hydroxy ester 82. 
In Specific Method 10, Boc-D-3,4-difluorophenylalanine 83 is deprotected by treatment with trifluoroacetic acid in CH2Cl2 to afford amino acid TFA salt 84. This intermediate is treated with sodium nitrite under mildly acidic aqueous conditions to provide hydroxy acid 85 in good yield. Compound 85 is esterified by exposure to either methanol or benzyl alcohol under acidic conditions to give hydroxy esters 86 and 87, respectively. 
In Specific Method 11, 2-ketobutyric acid (88) is subjected to an enzyme-mediated reduction process to afford hydroxy acid 89 in good yield.